Metabolomics and Risk of Parkinson's Disease (R01)

Title: Metabolomics and Risk of Parkinson's Disease-Mass Spec-Blood (Metabolomics)

PI Name: Alberto Ascherio

URL: https://pdbp.ninds.nih.gov/study_profile/248

Repository: Parkinson's Disease Biomarker Program

Status: Controlled Access

Funding Source: NIH-NINDS

Abstract: Parkinson disease (PD) is the second most common neurodegenerative disease in the United States and affects over one million Americans; this number is growing due to population aging. Current treatments do not prevent the disease progression that ultimately results in severe disability. There is thus a compelling need to develop neuroprotective treatments. Because at the time of the clinical diagnosis of PD there is already substantial neuronal loss, such treatments should ideally be initiated earlier. Aims of the proposed investigation are to implement and validate a novel metabolomic approach for the identification of early changes in peripheral blood of individuals with preclinical or premotor PD. The metabolomic results will be integrated with detailed and validated information on risk factors for PD, which has been collected prospectively and periodically updated. We expect by this means to identify new clues to the etiology of PD and to identify a metabolomic signature of PD that could contribute to an early diagnosis. To achieve these goals, we will take advantage of data and blood samples collected from over 80,000 participants in three large ongoing cohorts, the Nurses' Health Study (NHS), the Health Professional Follow-up Study (HPFS), and the Cancer Prevention Study-II Nutrition, who have been followed for over 25 years for incident Parkinson disease. We expect to include a total of 805 incident cases of PD that will be matched to 805 controls, using a nested case-control design. PUBLIC HEALTH RELEVANCE: Parkinson disease is a chronic progressive disease for which there is no cure - the loss of brain cells that leads to disability develops insidiously over many years, and by the time the disease is diagnosed it is already extensive and irreversible. To identify Parkinson disease years before it becomes clinically manifest, we are proposing a novel approach that will take advantage of the peripheral blood and detailed lifestyle and medical information collected from over 80,000 individuals who were followed for up to 25 years. By comparing the blood levels of hundreds of compounds between the blood of individuals who developed Parkinson disease and the blood of individuals of the same age and sex who remained healthy, we expect to make novel discoveries on the etiology of Parkinson disease and to be able to develop a method for the early identification of Parkinson disease in other populations.

Goals: Specific aims and hypotheses include: Aim #1 To examine the relation between individual metabolites with PD risk. We hypothesize that markers associated with PD risk include: i) markers associated with insulin resistance and risk of diabetes, such as circulating branched chain aminoacids (BCAA), choline, glutamate, or acylcarnitines, ii) other markers of mitochondrial dysfunction or oxidative dysregulation, including increases in plasma creatine, lactate, and alanine; and iii) urate. We will also explore individual metabolites not a priori hypothesized to be related to PD, and potential confounding or interactions between plasma urate and markers of insulin resistance, mitochondrial dysfunction or oxidative dysregulation. Aim #2 To conduct analyses of metabolic profiles. We hypothesize that these analyses will contribute to reveal novel specific biomarkers for PD, providing insights into important metabolic pathways. Further, we will use statistical learning techniques to identify a multimetabolite predictor of prodromal PD. For this step, discovery analyses will be conducted in 2/3 of the cases and validation in the remaining 1/3. Aim #3 To investigate whether known associations between lifestyle and PD risk are mediated by individual metabolites or metabolic profiles. We hypothesize that the known strong inverse associations between cigarette smoking and caffeine consumption and PD risk are mediated by changes in the plasma metabolome, and the increased risk associated with dairy consumption is mediated by decreased uricemia. Further, we will explore whether there are gender difference in metabolomics profiles related to PD risk. The proposed investigation will use archived blood specimens and will measure a well-validated panel of ~ 300 targeted metabolites developed by the Broad Institute of MIT and Harvard. The rich data on diet and lifestyle collected prospectively from participants in our cohorts are another unique feature that allows integrating the metabolomics data with information on risk factors for PD, such as smoking, coffee consumption, diet, and physical activity. Thus, in addition to the specific aims above, we will be able to explore a broad array of data and to relate exposures of interest to specific metabolomics profiles.

Study ID: PDBP-STUDY0000248

Repository URL: https://pdbp.ninds.nih.gov/

Data Type: Other-Omics

Study Type: Epidemiology

Study Started On: 2015-09-01

Study Completed On: 2020-06-30

Estimated number of Subjects: 1878